The introduction of highly active antiretroviral therapy (HAART) regimens in the mid-1990's has resulted in a 50% decline in AIDS death rates, and a 40-50% decrease in the incidence of HIV-associated dementia. Nonetheless, AIDS-associated neurological diseases including HIV-associated dementia (HIV-D) and sensory neuropathies (HIV-SN) continue to be major causes of morbidity and mortality. HIV-associated sensory neuropathies (HIV-SN) include distal sensory polyneuropathy (DSP) and dideoxynucleoside antiretroviral drug toxic neuropathy (ATN) and have emerged as the most common neurological complications in HIV infection, affecting 30% of AIDS patients. The development of HIV-SN represents an increasingly important treatment issue for HIV patients, affecting not only quality of life, but also limiting viral suppression strategies. Both HIV-D and minor cognitive-motor disorder remain very prevalent among HIV+ individuals with CD4 <200, with an estimated prevalence of 30%. This suggests that HAART does not provide complete protection against CNS or PNS damage in HIV/AIDS Numerous controlled treatment trials for both CNS and PNS disease in HIV/AIDS have been completed, mainly focusing on the use of antiretroviral agents for HIV-D, and symptomatic agents for HIV-SN. Only one trial of a potentially regenerative agent has been conducted for HIV-SN, but trials in HIV-D including 'adjunctive' agents thought to block critical pathophysiological cascades have produced significant improvements in memory. We theorize that there are common pathophysiological mechanisms in HIV-D and HIV-SN which might be addressed with a single agent. The neuroimmunophilin ligands, including GPI-1485, have several properties which make them attractive targets. The primary objective of this proposal is to facilitate the development of clinical trials of the neuroimmunophilin ligands both for HIV-D and HIV-SN. First, we will develop and validate novel models of human axonal regeneration, determining the kinetics and reliability of these human models. Then we will then incorporate as outcome measures into a Phase I/II trial of GPI-1485. Additionally, we will conduct a Phase UII trial of GPI-1485 in I-IIV-D. Our proposal is strengthened by our proven ability to characterize the duration and course of HIV-D and HIV-SN through the serial testing of individuals with advanced HIV infection. This proposal builds on established cohorts participating in longitudinal studies of HIV-1 infection in Baltimore.